The present invention is related to medical methods of treatment More particularly, the present invention concerns the use of (S)-3-ethyl-4-[(1H -imidazol-5-yl)methyl]-2-oxazolidinone, or a pharmaceutically acceptable salt thereof for the treatment of the symptoms of cognitive decline in an elderly patient including Alzheimer's disease.
(S)-3-Ethyl-4-[(1-methyl-1H-imidazol-5-yl)-methyl]-2-oxazolidinone is described by Sauerberg, P., et al (Journal of Medicinal Chemistry, 32, pages 1322-1326 (1989)). The compound is disclosed as a more stable analog of pilocarpine with cholinergic muscarinic agonist properties in vitro. The aforementioned compound is also disclosed by Gonzalez, F. B., et al (Tetrahedron Letters, 30, pages 2145-2148 (1989)). No biological properties were reported by Gonzalez, et al.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons. In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia for example, the level of the enzyme choline acetyltransferase (CAT) can be reduced as much as ninety percent (see Davies, P., et al The Lancet, 2, page 1403 (1976); Perry, E. K., et al, Journal of Neurological Sciences, 34, pages 247-265 (1977); and White, P., et al, The Lancet, 1, pages 668-670 (1977)).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic or acetylcholine-releasing nerve endings in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine levels or cholinergic function (i.e., cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction (Peterson, C. and Gibson, G. E., Neurobiology of Aging, 4, pages 25-30 (1983)). Aged humans and nonhuman primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine (see Davis, H. P., et al, Experimental Aging Research, 9, pages 211-214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effect as acetylcholine. Two other agents, pillocarpine and oxotremorine, have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action.
It is well known that the cholinergic hypothesis suggests that cholinomimetics, including muscarinic agents, may have potential in treating senile cognitive decline (SCD). However, the multiple development issues associated with cholinomimetics, including, for example, poor bioavailability, short duration of action, and especially parasympathetic side effects, have diminished hopes of adequate therapy with this class of agents.
We have now surprisingly discovered that (S)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxazolidinone also shows some selectivity for central muscarinic sites, which addresses side effects issues. Moreover, we have unexpectedly found that (S)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxazolidinone has good oral availability and a reasonable duration of action, which addresses other development issues common to cholinomimetics. Therefore, despite the limited or nonexistent utility of previous cholinomimetics as therapy for SCD (S)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2oxazolidinone has been found to be selective for M1 muscarinic receptors in the brain and thus is expected to be useful in the treatment of the symptoms of cognitive decline in an elderly patient including Alzheimer's disease.